Yong-Yu Liu

Publications (47) View all

• Chapter: The role of sphingolipids in modulating pluripotency of stem cells

  Salman B. Hosain, Ronald A. Hill, Yong-Yu Liu
  02/2013; , ISBN: 978-94-007-6210-7
• Source

  Available from: Suresh V Ambudkar

  Article: Ceramide Glycosylation by Glucosylceramide Synthase Selectively Maintains the Properties of Breast Cancer Stem Cells.

  Vineet Gupta, Kaustubh N Bhinge, Salman B Hosain, Katherine Xiong, Xin Gu, Runhua Shi, Mind-Yi Ho, Kay-Hooi Khoo, Su-Chen Li, Yu-Teh Li, Suresh V Ambudkar, S Michal Jazwinski, Yong-Yu Liu
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  ABSTRACT: Cancer stem cells (CSCs) are distinguished from normal adult stem cells by their stemness without tissue homeostasis control. Glycosphingolipids (GSLs), particularly globo-series GSLs are important markers of undifferentiated embryonic stem cells, but little is known whether or not ceramide glycosylation, which controls glycosphingolipid synthesis, plays a role in modulating stem cells. Here, we report that ceramide glycosylation catalyzed by glucosylceramide synthase (GCS), that is enhanced in breast cancer stem cells (BCSCs) but not in normal mammary epithelial stem cells, maintains tumorous pluripotency of BCSCs. Enhanced ceramide glycosylation and globotriosylceramide (Gb3) correlate well with the numbers of BCSCs in breast cancer cell lines. In BCSCs sorted with CD44+/ESA+/CD24- markers, Gb3 activates cSrc/β-catenin signaling and upregulates the expression of FGF-2, CD44 and Oct-4 enriching tumorigenesis. Conversely, silencing GCS expression disrupts Gb3 synthesis, and selectively kills BCSCs through deactivation of cSrc/β-catenin signaling. These findings highlight the unexploited role of ceramide glycosylation in selectively maintaining the tumorous pluripotency of CSCs. It speculates that disruption of ceramide glycosylation or globo-series GSL is a useful approach to specifically target BCSCs specifically.
  Journal of Biological Chemistry 08/2012; · 4.77 Impact Factor
• Article: The opposite effects of doxorubicin on bone marrow stem cells versus breast cancer stem cells depend on glucosylceramide synthase.

  Kaustubh N Bhinge, Vineet Gupta, Salman B Hosain, Seetharama D Satyanarayanajois, Sharon A Meyer, Benny Blaylock, Qian-Jin Zhang, Yong-Yu Liu
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  ABSTRACT: Myelosuppression and drug resistance are common adverse effects in cancer patients with chemotherapy, and those severely limit the therapeutic efficacy and lead treatment failure. It is unclear by which cellular mechanism anticancer drugs suppress bone marrow, while drug-resistant tumors survive. We report that due to the difference of glucosylceramide synthase (GCS), catalyzing ceramide glycosylation, doxorubicin (Dox) eliminates bone marrow stem cells (BMSCs) and expands breast cancer stem cells (BCSCs). It was found that Dox decreased the numbers of BMSCs (ABCG2(+)) and the sphere formation in a dose-dependent fashion in isolated bone marrow cells. In tumor-bearing mice, Dox treatments (5mg/kg, 6 days) decreased the numbers of BMSCs and white blood cells; conversely, those treatments increased the numbers of BCSCs (CD24(-)/CD44(+)/ESA(+)) more than threefold in the same mice. Furthermore, therapeutic-dose of Dox (1mg/kg/week, 42 days) decreased the numbers of BMSCs while it increased BCSCs in vivo. Breast cancer cells, rather than bone marrow cells, highly expressed GCS, which was induced by Dox and correlated with BCSC pluripotency. These results indicate that Dox may have opposite effects, suppressing BMSCs versus expanding BCSCs, and GCS is one determinant of the differentiated responsiveness of bone marrow and cancer cells.
  The international journal of biochemistry & cell biology 06/2012; 44(11):1770-8. · 4.89 Impact Factor
• Article: Doxorubicin and MBO-asGCS oligonucleotide loaded lipid nanoparticles overcome multidrug resistance in adriamycin resistant ovarian cancer cells (NCI/ADR-RES).

  Akhtar Siddiqui, Vineet Gupta, Yong-Yu Liu, Sami Nazzal
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  ABSTRACT: The objective of this study was to increase the potency of doxorubicin against adriamycin-resistant NCI/ADR-RES cells by concurrent treatment with doxorubicin and MBO-asGCS loaded solid-lipid nanoparticles (SLN). Loading doxorubicin as ion-pair complex with deoxytaurocholate into cationic and neutral SLN was investigated. Fast release and poor entrapment were observed in cationic nanoparticles, which were corrected by entrapping the complex in neutral polyoxyethylene (20) stearyl ether (Brij(®) 78)/VitE-TPGS nanoparticles. Slow doxorubicin release confirmed the influence of charge and electrolytes on the dissociation of ion-pair complexes. To evaluate antitumor activity, NCI/ADR-RES cells were treated with separate SLN: one loaded with doxorubicin and another carrying MBO-asGCS oligonucleotide. The viability of cells treated with 5 μM doxorubicin was reduced to 17.2% whereas viability was reduced to 2.5% for cells treated with both 5 μM doxorubicin SLN and 100 nM MBO-asGCS SLN. This suggested enhanced apoptosis due to sensitization and effective intracellular delivery of MBO-asGCS and doxorubicin by SLN.
  International journal of pharmaceutics 04/2012; 431(1-2):222-9. · 2.96 Impact Factor
• Article: Direct quantitative determination of ceramide glycosylation in vivo: a new approach to evaluate cellular enzyme activity of glucosylceramide synthase.

  Vineet Gupta, Gauri A Patwardhan, Qian-Jin Zhang, Myles C Cabot, S Michal Jazwinski, Yong-Yu Liu
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  ABSTRACT: Glucosylceramide synthase (GCS or GlcT-1), converting ceramide to glucosylceramide, is a key enzyme for the synthesis of glycosphingolipids. Due to its diverse roles in physiology and diseases, GCS may be a disease marker and drug target. Current assays for enzymes including GCS are based on reactions conducted in a test tube using enzyme preparations. Measurement of enzyme activity in laboratory-made conditions cannot directly evaluate the role of GCS in cells. Here, we introduce a new approach to determine GCS cellular activity using fluorescent NBD C6-ceramide in vivo. Cellular GCS transfers UDP-glucose to NBD C6-ceramide and produces NBD C6-glucosylceramide. C6-glucosylceramide is then separated from C6-ceramide by thin-layer chromatography and both are then quantitated by spectrophotometer. This cell-based method is able to quantitate glucosylceramide in pmol range, produced by approximately 50,000 cells or 1.0 mg tissue. This method has been used successfully to evaluate the degrees of GCS enzyme in cells and in tumors subjected to gene manipulation and chemical inhibition. These data indicate that this cell-based fluorescent method is direct, reproducible, and simple for assessing ceramide glycosylation. It is applicable to validate GCS activity in drug-resistant cancers and in other disorders.
  The Journal of Lipid Research 10/2009; 51(4):866-74. · 5.56 Impact Factor